Letter
pubs.acs.org/JPCL
Comparing Charge Transport in Oligonucleotides: RNA:DNA Hybrids
and DNA Duplexes
Yuanhui Li,† Juan M. Artés,†,∥ Jianqing Qi,‡ Ian A. Morelan,§,⊥ Paul Feldstein,§ M. P. Anantram,‡
and Joshua Hihath*,†
†
Electrical and Computer Engineering Department, University of California Davis, Davis, California 95616, United States
Department of Electrical Engineering, University of Washington, Seattle, Washington 98195, United States
§
Department of Plant Pathology, University of California Davis, Davis, California 95616, United States
‡
S Supporting Information
*
ABSTRACT: Understanding the electronic properties of oligonucleotide systems is
important for applications in nanotechnology, biology, and sensing systems. Here the
charge-transport properties of guanine-rich RNA:DNA hybrids are compared to doublestranded DNA (dsDNA) duplexes with identical sequences. The conductance of the
RNA:DNA hybrids is ∼10 times higher than the equivalent dsDNA, and conformational
differences are determined to be the primary reason for this difference. The conductance of
the RNA:DNA hybrids is also found to decrease more rapidly than dsDNA when the length
is increased. Ab initio electronic structure and Green’s function-based density of states
calculations demonstrate that these differences arise because the energy levels are more
spatially distributed in the RNA:DNA hybrid but that the number of accessible hopping
sites is smaller. These combination results indicate that a simple hopping model that treats
each individual guanine as a hopping site is insufficient to explain both a higher conductance
and β value for RNA:DNA hybrids, and larger delocalization lengths must be considered.
structure.29 The RNA:DNA hybrid is predominantly in the Aform, while dsDNA is typically in the B-form under
physiological conditions.30,31 As such, the electronic overlap
between the π orbitals in the bases will be different, which
could lead to substantial differences in the charge-transport
properties of RNA:DNA hybrids compared with those of
dsDNA. Given both the biological significance of RNA and
RNA:DNA hybrids, the similarities in structure, and selfassembly properties of these systems to DNA, it is important to
explore the electronic properties of these systems for both
molecular electronics and biosensor applications.
Driven by the importance of this vital molecule, various
experimental and theoretical approaches have been employed
to understand charge transfer in RNA:DNA using photochemical31−33 and electrochemical34,35 measurements. Alternatively, in this work, we directly study the conductance
properties of RNA:DNA hybrids and compare them with
identical dsDNA duplexes at the single-molecule level using the
scanning tunneling microscope (STM)-break junction technique in a buffered solution.36 This technique has been
extensively applied to study charge transport through organic
and biological molecules.37−41 It provides the advantages of
being able to work in an aqueous, controllable environment,
and collecting thousands of conductance measurements in a
DNA has long been espoused as the molecule of life,1 and given
its unique structural and self-assembly properties it is often
proclaimed as an important material for nanotechnology.2−4
Because of this substantial promise, a great deal of research has
focused on both its mechanical5−7 and electrical8−13 properties.
Meanwhile, our understanding of the biological importance of
RNA has also continuously increased in recent decades. It is
now known that RNA plays a pivotal role in gene expression
and regulating biochemical reactions within the cell,14 and it is
the messenger between DNA and ribosomes and proteins.15,16
Recently, it has also been determined that RNA is even
involved in the immunological responses of many organisms.17,18 To fulfill these roles, RNA can assemble with
complementary DNA strands to form RNA:DNA hybrids
that are integral to many biological processes, including DNA
replication,19−21 transcription during gene expression,22 and
reverse transcription.23,24 Although chemically similar, singlestranded (ss) RNA differs from ssDNA in a couple of important
ways. First, in RNA, uracil bases replace the thymine bases
found in DNA, and second the backbones are different with
RNA having a ribose group instead of the deoxyribose that is
present in DNA. Despite these differences, RNA:DNA hybrids
are capable of forming a double helix, with the base pairs (bp)
arranged in a π stack,25,26 in a way analogous to dsDNA.
dsDNA has been well-documented to allow long-range charge
transport through the π stack under certain conditions.26,27
Therefore, it is expected that RNA:DNA hybrids will also
transport charge;28 however, the structure of the RNA:DNA
helix is significantly different from the common B-form dsDNA
© 2016 American Chemical Society
Received: April 7, 2016
Accepted: May 4, 2016
Published: May 4, 2016
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Figure 1. Length dependence of RNA:DNA and dsDNA conductance. (a) Schematic of the guanine-rich sequences used for length dependence
studies for RNA:DNA and dsDNA. (b) Idealized schematic of the experimental setup showing a 15-bp RNA:DNA molecule bound between two
gold electrodes with amine linkers (shown as green spheres). (c,d) Conductance histograms for each of the RNA:DNA and dsDNA molecules
studied, respectively. The arrows indicate the conductance peak for each sequence. (Note that histograms are offset vertically and the tails of some
histograms are cut for clarity. Please see Figure S2 for the completed histograms). (e) Natural logarithm of conductance versus length for RNA:DNA
(blue squares) and B-form dsDNA (black circles). Error bars are full widths at half-maximum (fwhm) for the conductance peaks.
relatively short time period. As such, this technique enables the
statistical analysis of the most probable conductance values for
a single-molecule junction in a known environment. In the past
decade, this technique has been used to obtain reproducible
conductance values for biomolecules such as dsDNA,13,42−47
peptides,48,49 and proteins.50,51
We present a systematic study of the charge-transport
properties of individual RNA:DNA and dsDNA duplexes in a
sodium phosphate buffer solution using the STM-break
junction technique.52 We study a series of G:C-only RNA:DNA
sequences (GGG-C(GC)n-GGG, with n = 1−5) and the
identical dsDNA sequences with n = 1−4 and extract their
length-dependent exponential decay constants (β values). We
find that the conductance of each RNA:DNA sequence is
approximately 1 order of magnitude higher than that of the Bform dsDNA with the same sequence and demonstrate that the
conformational differences between the two duplexes play a
pivotal role in the transport properties. We use circular
dichroism (CD) spectroscopy to confirm that the conformations of the two oligonucleotides are different (A form and B
form for RNA:DNA and dsDNA, respectively). Furthermore,
by inducing the A-form in dsDNA using a 75% ethanol solution
we are able to increase the conductance of the dsDNA to a
similar level as the RNA:DNA hybrid, thus confirming that the
transport differences between the two duplexes are primarily
due to changes in the structure rather than the composition.53
To understand the differences in the structural and electrical
properties of both oligonucleotides we use ab initio electronic
structure calculations to conclude that differences in absolute
conductance and β value between RNA:DNA and dsDNA are
primarily due to their structural differences. These results
demonstrate that electronic-transport studies are capable of
extracting relevant structural and biological information from a
hybrid oligonucleotide duplex and thus open the door for
further studies on conductance-based RNA detection.
To examine the charge-transport properties of RNA:DNA
hybrids, we have explored the length dependence of the
conductance of these molecules and also measured the
conductance of the equivalent dsDNA duplexes for comparison. The conductance of a tunneling junction can be
represented by G = Gce−βL, where Gc is the contact
conductance, β is the tunneling decay constant, and L is the
distance between the electrodes. The value of the decay
constant, β, is often used as a figure of merit to provide insights
into the charge-transport properties of the system. A large β
value indicates a substantial decrease in conductance with
increasing length and is typically used as an evidence of a
single-step tunneling process.54 Alternatively, a small β value
means that the conductance decreases less strongly with length
and is often used as an indication of a hopping mechanism.13
Thus, we performed break-junction measurements on the series
of RNA:DNA duplexes previously described, with n = 1−5, and
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on the identical dsDNA sequences with n = 1−4 (see Figure
1a). We modify both the 5′ and 3′ ends of the DNA strand with
amine linkers to ensure a good binding between the RNA:DNA
hybrid and the gold electrodes used in the STM38,55 (see SI).
Figure 1b illustrates a schematic of the measurement system
with a 15-bp DNA:RNA molecule linked between the gold tip
electrode and the gold substrate. With this break junction
technique, thousands of individual conductance measurements
can be obtained rapidly for statistical analysis, allowing the most
probable conductance of a single molecule to be determined by
adding all of the traces with steps to a conductance histogram.
The conductance histograms for each of these RNA:DNA (9−
17 bp) and dsDNA (9−15 bp) duplexes are shown in Figure
1c,d, respectively. The conductance histograms for each duplex
show a single, pronounced peak. From these plots, two
observations can be readily made. First, these plots allow direct
comparison between the RNA:DNA hybrids and the dsDNA,
and it is clear that for each specific sequence the conductance of
the RNA:DNA hybrid is about 10 times higher than the
equivalent dsDNA duplex. Second, it is apparent that the
conductance peak shifts to lower conductance values with
increasing lengths. By plotting the natural log of conductance
versus molecular length (Figure 1e), it is possible to obtain the
β values. This process yields a β value of 0.31 Å−1 for
RNA:DNA hybrids (Figure 1e, blue) and 0.20 Å−1 for dsDNA
duplexes (Figure 1e, black). Although these β values are
different, both are consistent with a hopping-based transport
mechanism,56 which has previously been reported for GC-rich
dsDNA sequences.31 Additional control experiments performed
on solutions containing only the single-stranded DNA with
amine linkers, only single-stranded RNA, and RNA:DNA
hybrids without linkers did not result in obvious peaks in the
experimentally accessible conductance range (Figure S1).
As previously mentioned, although the sequences are
identical for both duplexes, the conductance of each RNA:DNA
hybrid is higher than the respective dsDNA duplex. This
difference could be due to either conformational or chemical
differences. The chemical difference between the two molecules
is the addition of a hydroxyl group on the ribose in the case of
the RNA strand; however, the charge transport is expected to
be through the π system,27,57 and the bases of RNA:DNA and
dsDNA are the same in these sequences (no uracil is included).
Thus, this chemical difference is not expected to significantly
affect the charge-transport properties of these systems.
Therefore, we focus on the structural differences between the
two molecules instead of the chemical difference. RNA:DNA
hybrids are well known to be stabilized in the A-form,58 while
dsDNA is expected to adopt the B-form conformation in
buffered solutions.30,35 To verify this point, we performed CD
spectroscopy on both of the duplexes in a 100 mM sodium
phosphate buffer solution (Figure 2a). The primary indicator of
the A-form conformation is the appearance of an intense
negative peak at 210 nm,58 and this peak is clearly visible in the
RNA:DNA hybrid (Figure 2a, blue). We expect this structural
difference to be the dominant cause of the conductance
differences between these two duplexes, as recently demonstrated for A-form and B-form dsDNA.53
To test this hypothesis, we also examined the CD spectrum
and conductance of the 11-bp dsDNA duplex in the A-form
conformation by solubilizing it in a 75% ethanol solution (v/v)
to compare with both the RNA:DNA hybrid and the B-form
dsDNA. Figure 2a (green) shows the CD spectrum of the 11bp dsDNA in ethanol solution. Although there are some
Figure 2. Structure induced conductance differences. (a) CD spectra
of a RNA:DNA hybrid (blue), A-form dsDNA (green), and B-form
dsDNA (black) duplexes. (b−d) Conductance histograms of a GGGCGCGC-GGG sequence in the case of an RNA:DNA hybrid, A-form
dsDNA, and B-form dsDNA, respectively. Red curves are the Gaussian
fitting of the conductance peaks. The right schematics correspond to
the junctions formed with the different conformations for each
molecule.
differences between the 11-bp DNA duplex in ethanol and the
RNA:DNA hybrid (Figure 2a, blue), which can be attributed to
the effect of ethanol on the absorption properties,30,59 there is a
clear negative peak at 210 nm, indicating the stabilization of the
A-form conformation in this solution. By comparing individual
conductance histograms of RNA:DNA hybrids, A-form dsDNA,
and B-form dsDNA, as shown in Figure 2b−d, we find that the
conductance of 11-bp RNA:DNA hybrid is very similar to the
conductance of A-form dsDNA and that both of these are ∼10
times higher than B-form dsDNA, thus verifying that the
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family studied (from the first to eighth bp), but for RNA:DNA
series they are distributed through the entire molecule,
regardless of length. These results show that all of the base
pairs contribute to the HOMO level in the RNA:DNA case,
while in the B-form contribution drops off rapidly after the first
G triplet. This indicates a higher delocalization of the HOMO
orbital in the RNA:DNA case.
This difference in the distribution and contribution of the
HOMO level to the electronic structure can be visualized by
examining the differences in the DoS in the two systems. Figure
3d shows the ratio of the 2D DoS of the RNA:DNA hybrid to
the B-form dsDNA near HOMO level along the entire length
of the 11-bp sequences. For these plots the HOMO level of
each molecule is set to zero energy, and the DoS is plotted as
both a function of both energy (ordinate) and molecular length
(abscissa). From these plots it is apparent that in GGG triplet
regions on each end the DoS are similar in both cases (ratio is
close to 1); however, in the central bridge region (alternating
GC sequence in the dashed box), it is clear that near the
HOMO level the DoS in the RNA:DNA hybrids is much larger
(as much as 104 times greater) than the DoS for dsDNA in this
region. Along with the isosurface plots (Figure 3a,b) and the
projected HOMO distribution (Figure 3c), these results
suggest that for a given number of bp’s, charge should
transport more efficiently (have a higher conductance) in the
RNA:DNA hybrid case (A-form) than in the B-form dsDNA
case. This result is consistent across the entire range of
molecules studied (Figure S3).
Next, we turn our attention to the question of why the
conductance decreases more rapidly (larger β value) in the
RNA:DNA hybrid than in the B-form DNA case. As previously
noted, the low β values in both cases are consistent with a
hopping transport mechanism, and in DNA it has often been
assumed that because guanines have the lowest oxidation
potential each guanine in the system will act as an individual
hopping site;61 however, it has also been noted that a charge
carrier could be delocalized over more than one base and that
the transport may include both incoherent and coherent
components.28,62−64 In the discussion above, we demonstrated
that the energy levels can be distributed over several base pairs
in each duplex, indicating that it is insufficient to treat each
guanine individually as a hopping site for either of these
systems. As such, in these molecules, the number of hopping
sites is likely not simply the number of base pairs or guanines in
the system but instead depends on both the spatial and energy
distribution of the system’s energy levels. This fact in turn
indicates that the charge carriers may require fewer total hops
to transport across the entire molecule. In this case, the number
of hopping sites may be different for each of the
oligonucleotide duplexes, a detail that will have important
impacts on the transport properties and the β value.
To examine this possibility more closely and determine how
it relates to the difference in the β values between the two
systems, we examine 2D DoS plots in Figure 4 for all
RNA:DNA and dsDNA sequences with a coupling term (Γ =
100 meV) between the molecule and both gold electrodes.
These plots display both the spatial and energy distribution of
the states, and the z-color scale indicates the density of states at
each position. Here we focus on the energy range below the
HOMO level because the transport is expected to be
dominated by hole transport.65−67 The bright horizontal stripes
represent the spatial distribution of each of the Kohn−Sham
energy levels for the molecular system, and again the HOMO
primary difference in the transport properties of these
molecules is structural rather than chemical.
Interestingly, both the conductance and the β value of
RNA:DNA are larger than B-form dsDNA. To understand how
the structural differences between these duplexes relate to these
effects, we have performed a series of electronic structure
calculation using first-principles calculations (Gaussian 09
software package with the B3LYP/6-31G(d,p) functional and
basis set) coupled to Green’s function techniques60 to examine
the changes in the energy levels and determine the density of
states (DoS) for these molecules.
We have recently demonstrated that A-form DNA is higher
in conductance than B-form DNA due to an increased spatial
distribution of energy levels in the A-form, coupled to an
increase in the DoS around the highest occupied molecular
orbital (HOMO) level in this configuration.53 Given the
similarities in structure and conductance values between A-form
DNA and RNA:DNA hybrids, we hypothesize that a similar
effect causes the conductance difference seen here. To examine
this possibility, in Figure 3a,b we present the HOMO isosurface
Figure 3. Results from charge-transport simulations of 11-bp
RNA:DNA and B-form dsDNA. (a,b) 3D isosurface of the HOMO
orbital (isovalue = 2 × 10−5) on the oligonucleotide structures for
RNA:DNA and B-form dsDNA. (c) Projection of the HOMO level
onto each of the base pairs in the A-form RNA:DNA (blue solid line)
and B-form dsDNA (black solid line). There is no contribution to the
HOMO level for the 9th to 11th base pairs in dsDNA. (d) 2D
representation of the ratio of the total density of states (DoS) along
the molecule between RNA:DNA hybrids and B-form dsDNA for an
energy ranging from HOMO−0.1 to 0.5 eV above HOMO level.
plots of the 11-bp sequence for both the RNA:DNA hybrids
and the B-form dsDNA with an isovalue of 2 × 10−5. At this
value the HOMO level is distributed over ∼70% of the length
of the RNA:DNA hybrid and over only ∼50% of the length of
the B-form dsDNA. This effect can be seen more quantitatively
by examining the projection of the HOMO level onto each of
the base pairs in the duplex (Figure 3c). Additionally, as shown
in Figure S4, the HOMO levels are distributed through
approximately the same number of bp’s for the entire dsDNA
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Figure 4. 2D total DoS along the molecule of (a) 9-bp, (c) 11-bp, (e) 13-bp, and (g) 15-bp RNA:DNA hybrid and (b) 9-bp, (d) 11-bp, (f) 13-bp,
and (h) 15-bp B-form dsDNA, respectively, for an energy ranging from HOMO−0.5 to 0.1 eV above HOMO level. The 1D energy-level plots are
shown on the right side of each plot. (HOMO = 0 eV in all cases). In this energy window, there are many more energy levels for dsDNA than in
RNA:DNA for each length.
several kBT) suggests that there are few energy levels close to
the HOMO-level that are accessible as hopping sites.
Furthermore, as the length increases, the number of potential
hopping sites does not significantly increase throughout the
RNA:DNA series (Figure 4a,c,e,g). Alternatively, in the B-form
DNA case, there are many potential hopping sites (energy
levels), and this number increases with increasing length
(Figure 4b,d,f,h). The smaller number of accessible hopping
sites, coupled to the larger energy separation between them, is
level is taken as zero energy in each case. In these plots, each of
the energy levels (molecular orbitals) is distributed over several
base pairs, in agreement with the isoplots in Figure 3a,b. The
lines next to each of the 2D DoS colormaps indicate the values
of the calculated energy levels and show that the levels are more
distributed in energy for the RNA:DNA hybrids. This
separation will result in weaker coupling between the levels
than in the B-form DNA case.6 Additionally, because the energy
levels in the RNA:DNA case are more sparse (separated by
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■
expected to result in a larger β value in the RNA:DNA hybrid
case.
In summary, we have measured the conductance of
individual RNA:DNA hybrids using the STM break junction
technique in aqueous solution. We show that the conductance
of these G:C-rich RNA:DNA hybrids is approximately 1 order
of magnitude higher than the equivalent dsDNA sequence. We
attribute this to their conformational differences rather than
chemical differences. We demonstrate that the conformations
of RNA:DNA and B-form dsDNA are significantly different
using CD spectroscopy and confirm this effect as the origin of
the conductance difference by comparing the RNA:DNA
hybrid to the A-form DNA duplex. Length-dependent
conductance studies suggest that the charge-transport mechanism in both oligonucleotides is dominated by hopping. These
observations are accounted for by using ab initio electronic
structure calculations coupled to Green’s Function-based DoS
calculations, which reveal that simple nearest-neighbor hopping
between guanine bases is insufficient to accurately treat the
transport behavior. The theoretical calculations of projected
HOMO distributions show that the HOMO level is more
distributed along the molecules in RNA:DNA duplexes, which
suggests a higher conductance than dsDNA. The 2D DoS
calculations also provide additional insights into both the spatial
and energy distribution of the molecular orbitals. From these
plots it is clear that fewer hopping sites are available in the
RNA:DNA duplex case and thus result in a higher distance
decay factor as the length increases. Given the importance of
RNA in biological systems, this electrical measurement of RNA
could open the door to single-molecule sensors with
applications in the fundamental biomedical research and
genetic diseases diagnosis.
■
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ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jpclett.6b00749.
Control experiments, complete conductance histograms
of RNA:DNA and dsDNA, 2D ratio of DoS calculations,
projection of HOMO level calculations; experimental
details of sample preparation and measurements, and
computational simulation procedure. (PDF)
■
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected].
Present Addresses
∥
J.M.A.: Faculty of Sciences, Vrije Universiteit, 1081 HV
Amsterdam, The Netherlands.
⊥
I.A.M.: Department of Integrative Biology, Oregon State
University, Corvallis, Oregon 97331, United States.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Y.L., J.M.A., I.A.M., P.F., and J.H. acknowledge the University
of California, Davis RISE program and the National Science
Foundation (ECCS-1231915). J.Q. and M.P.A. acknowledge
support from the National Science Foundation under Grant
No. 102781.
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DOI: 10.1021/acs.jpclett.6b00749
J. Phys. Chem. Lett. 2016, 7, 1888−1894